HUWE1-mediated ubiquitination and degradation of oxidative damage repair gene ATM maintains mitochondrial quality control system in lens epithelial cells.

Abstract

Mitochondrial dysfunction, resulting from a diminished oxidative damage repair capacity of mitochondrial DNA (mtDNA) in peripheral lens epithelial cells (LECs), is a key pathogenic mechanism in age-related cortical cataract (ARCC). This study aims to investigate the potential role of the E3 ligase HUWE1 and its ubiquitination substrate, the oxidative damage repair gene ATM, in the pathogenesis of ARCC. Our findings reveal that ATM protein expression is downregulated in human peripheral lens epithelial cells and the turbid cortex, correlating with increased expression of HUWE1. Overexpression of ATM is shown to repair damaged mtDNA, protect mitochondria in LECs from oxidative damage, inhibit mitochondrial fission, enhance mitochondrial biogenesis and mitophagy, and prevent LECs apoptosis. Conversely, overexpression of HUWE1 may negate the protective effects of ATM via the ubiquitination pathway, promote oxidative stress-induced mitochondrial damage, increase the expression of mitochondrial fission proteins Drp1/Fis1, lead to mitochondrial network fragmentation and LECs apoptosis. In a SD rat lens model ex vitro, the ATM inhibitor AZD0156 exacerbated lens opacity, whereas the mitochondrial fission inhibitor Mdivi-1 restored lens transparency. These results suggest that modulating key molecules involved in oxidative damage repair and mitochondrial fission pathways could enhance mitochondrial quality control, paving the way for the development of targeted molecular therapies for the prevention and treatment of ARCC.